Arachidonic acid and its metabolites regulate many key functions in the repair of skin injury, such as vasodilation, chemotaxis, and immunomodulation. Ultraviolet light B (UVB) exposure is a particularly common form of skin injury, which is associated with increased synthesis of eicosanoids. The mechanisms of enhanced synthesis are poorly understood. Recent data obtained in my laboratory indicate that endogenous release of histamine in human skin explants mediates 60% of the increased prostaglandin synthesis in the early period (up to 8 hours) after UV exposure. Studies of epidermal cultures indicate that UV-induced potentiation of histamine-stimulated prostaglandin synthesis involves an increase in the cellular capacity for prostaglandin synthesis, an increase in sensitivity to histamine and calcium influx. However, these UV-induced events must result from photochemical reactions in epidermis. We propose to test the hypothesis that peroxidative injury by UV light increases release of esterified fatty acids through the action of phospholipases A2 and C with consequent activation of protein kinase C. Preliminary data clearly suggest that protein kinase C activation has occurred in UV-injured keratinocytes. In addition, we propose that the normal calcium compartmentalization present in skin is disrupted in UV injury, increasing the availability of calcium to potentiate agonist- induced prostaglandin release. The agonist histamine, which we know stimulates prostaglandin synthesis, and which preliminary data show is synthesized by keratinocytes in UV injury, will be used to dissect these mechanisms. The long-term objective of these studies is to provide the necessary foundation to develop therapy for UVB-induced skin injury. This objective is based on the hypothesis that mechanisms leading to enhanced PGE2 synthesis are important in the pathogenesis of UVB injury.